The present invention relates to inhibitors of enzymes that catalyse the interconversion of active and inactive glucocorticoids, compositions comprising the inhibitors, kits and articles of manufacture comprising the inhibitors and compositions, methods of making the inhibitors and compositions, and methods of using the inhibitors and compositions. The inhibitors and compositions comprising them are useful for treating or modulating diseases in which enzymes that catalyse the interconversion of glucocorticoids may be involved, symptoms of such diseases, or the effect of other physiological events mediated by these enzymes. Accordingly, the invention also provides for methods of treating diseases in which one or more enzymes that catalyse the interconversion of glucocorticoids is involved.
Short-chain dehydrogenases/reductases are a family of reversible NAD(H)/NADP(H) dependent oxidoreductases that interconvert active and inactive glucocorticoids. For example, 11β-Hydroxysteroid Dehydrogenase Type 1 (11b-HSD1) belongs to the short-chain dehydrogenase/reductase family of enzymes. Specifically, 11b-HSD1 catalyses the conversion of inactive and active glucocorticoids in a number of tissues and organs including adipose tissue, liver, bone, pancreas, endothelium, ocular tissue, muscle and parts of the central nervous system (Tomlinson et al., Endocr. Rev., 25 (5), 831-66 (2004)).
11b-HSD1 has been implicated in type-2 diabetes, osteoporosis, hypertension, ocular disorders, cognitive disorders, the metabolic syndrome and other metabolic disorders. The non-specific 11b-HSD1 inhibitor carbenoxolone increases insulin sensitivity in healthy, lean, humans as well as those with the symptoms of type-2 diabetes (Andrews et al., J. Clin. Endocrinol. Metab., 88 (1), 285-91 (2003)). Mice that overexpress 11b-HSD1 in adipocytes develop hyderlipidemia, insulin resistance and visceral obesity. This phenotype has been shown to resemble the human metabolic syndrome (Masuzaki et al., Science, 294 (5549), 2166-70 (2001)). 11b-HSD1 knockout mice have shown resistance to developing obesity-induced, and stress-induced, insulin resistance as well as displaying decreased HDL-cholesterol and VLDL triglycerides (Kotelevtsev et al., Proc. Natl. Acad. Sci. USA, 94 (26), 14924-29 (1997)). These findings have stimulated interest in inhibitors of 11b-HSD1 as potential drugs for the treatment of disorders where a decreased level of active intracellular glucocorticoid is desired.
There is a continued need to find new therapeutic agents to treat human diseases. The hydroxysteroid dehydrogenases, specifically but not limited to 11β-Hydroxysteroid Dehydrogenase Type 1, are especially attractive targets for the discovery of new therapeutics due to their important role in type-2 diabetes, osteoporosis, hypertension, ocular disorders, cognitive disorders, the metabolic syndrome and other metabolic disorders.